Pathological, biochemical and genetic studies have implicated the Abeta peptide in the pathogenesis of Alzheimer's disease and suggested that reducing Abeta in the brain should be therapeutic.
One method for reducing Abeta in the brain is vaccination, first demonstrated by Shenk and colleagues who used Aβ 1-42 as an active vaccine and succeeded in reducing amyloid load in a mouse model of AD. It was then shown that the use of beta amyloid 1-42 as an active vaccine not only induced an effective remission of beta amyloid plaques in the brain but also led to cognitive and behavioral improvements. Additionally, passive immunotherapy was also shown to lead to similar results as the active beta-amyloid vaccine study.
Although vaccination was clearly effective in the mouse models of AD, the increased presence of antigen-presenting, HLA-DR-positive and other immunoregulatory cells together with increased levels of inflammatory cytokines and acute phase reactants in the vicinity of the neuropathology indicated that the vaccination triggered an inflammatory immune response
The few mutations in the APP gene that result in mutant Aβ peptides cause special forms of autosomal dominant AD. For example, the Dutch and Flemish mutations are known to cause patterns of aggregation that strongly differ from those with wild type Aβ peptide and result in different clinical manifestations of the disease. The increased success with vaccinations using amyloid β peptide in mouse models of AD encouraged a human clinical trial. The trial was a randomized, multi-centered, placebo-controlled, double-blind trial using wild type amyloid beta 1-42 peptide, termed AN1792, as a vaccine in combination with the adjuvant QS-21 and polysorbate 80 as stabilizer. The trial included patients aged 50 to 85 years with probable AD, as determined by the Mini-Mental State Examination (MMSE). Phase II of the trial was suspended due to an occurrence of meningoencephalitis in a small (6%) subset of patients. However, in a follow up study of the vaccinated patients, some clinical benefits of the vaccination including reduced AD-like pathology and improved cognition in the patients could be demonstrated. In addition, there were indications that the inflammatory response might actually have been triggered by the adjuvant or the stabilizer and not the antigen. Further analysis is required to determine the mechanism of the vaccine-induced neuroinflammation and the associated meningoencephalitis.
It has been theorized that the Alzheimer's disease related inflammation could be a form of autoimmunity that potentially marks a more specific and progressive state of the disease. Preliminary data, such as the measurement of pro-inflammatory cytokines after vaccination with and without adjuvant, suggests that the causes of many of the brain tissue inflammation side effects of the vaccines are possibly due to the adjuvants that carry the antigen. In fact, other studies have shown that adjuvants induce significant pro-inflammatory cytokine expression in vivo including up-regulation of TNF-α, IFNγ, and IL-4 even without being co-delivered with an antigen.
Another problem associated with the adverse effects of vaccination is related to the T cell epitope that resides in the Aβ 1-42 peptides. Thus, numerous approaches have been proposed for vaccine development. A derivative Abeta peptide without a T cell epitope has been applied with different methods. In addition, viral delivery, Abeta combined with bacterial toxins, and DNA vaccines are all applied with the goal to develop a safe vaccine.
There are mounting evidences indicates that the Aβ 1-42 peptide and Aβ 1-40 peptide, generated from Amyloid precursor protein (APP), are the major etiological factors for AD. These peptides are the main constituents of the amyloid deposits found in AD patient's brains. Aβ 1-42 was used as an active vaccine to effectively remove beta amyloid plaques in the brain. Corresponding behavioral improvements were also observed. Passive immunotherapy by using antibodies against Aβ 1-42 peptide/protein can effectively inhibit the deposition of Aβ in the brain and this has significantly decreased memory deficits in an APP/PS1 transgenic mouse model.
The effectiveness of the peptide therapy approach in clearance of plaque in the mouse model and in patients is not in question. The hope for AD vaccine is to find a solution to the adverse effects caused by vaccine in humans. However, the pathological role of Beta amyloid in AD obviously remains strong and beta amyloid is currently the gold standard for evaluating treatment. Regardless of which method is used to treat AD, the most prominent factor is still beta amyloid peptide levels in vivo, so a safer and effective vaccine remains a very promising and cost-effective approach to either curing AD patients or at least ameliorating AD development.